Guidelines developed by the National Cholesterol Education Program's Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, as reported in Arch. Intern. Med., 148, 36 (1988), identified elevated cholesterol and low-density lipoprotein cholesterol (LDL-C) concentrations as the major targets for cholesterol-lowering therapy. The importance of cholesterol reduction in patients with overtly manifest coronary artery disease cannot be overstated, since virtually every major epidemiologic study performed to date has shown a significant correlation between the level of serum cholesterol at the time of entry and the risk of subsequent coronary disease. For example, see J. C. Rosa, Circulation, 81, 1721 (1990).
The results of 22 randomized cholesterol-lowering clinical trials to reduce the risk of coronary heart disease indicate an average reduction of 23 percent in the risk of non-fatal myocardial infarction and cardiac death in treated compared with control patients. In particular, a 10 percent decrease in the cholesterol level was associated with a reduction of approximately 20 percent in the incidence of new coronary events (S. Yusef et al., JAMA, 260, 2259 (1988)).
Present therapeutic guidelines include the recommendation that cholesterol-lowering drugs should be considered when cholesterol and low density lioprotein-cholesterol (LDL-C) levels remain significantly elevated after six months of appropriate dietary therapy. For example, see "National Education Programs Working Group Report on the Management of Patients With Hypertension and High Blood Cholesterol," Ann. of Intern. Med., 114, 224 (1991). Currently available hypolipidemic agents include bile acid sequestrants (cholestyramine and cholestipol), nicotinic acid, probucol, fibric acid derivatives (gemfibrizol and clofibrate), HMG-CoA reductase inhibitors, and the omega-3 unsaturated fatty acids found in various fish oil supplements. To date, no other classes of lipid-lowering agents have been approved for clinical use.
However, these agents have been associated with side effects that can deter or preclude their usage by many patients. For example, colestyramine and cholestipol are associated with constipation and abdominal discomfort. Cholestyramine can cause vitamin K, A and D deficiencies. Probucol clofibrate and gemfibrizol can cause diarrhea, abdominal pain and nausea, and the first two agents have been associated with arrhythmias.
Therefore, a need exists for new agents which are effective to lower blood cholesterol total triglycerides and/or LDL-C.